Sodium gamma-hydroxybutyrate (GHB or sodium oxybate) is a naturally occurring metabolite of many mammalian tissues (Fishbein et al, J. Biol Chem. 239:357-61 (1964), Mamelak, Neurosci Biobehav Rev. 13(4):187-98 (1989), Nelson etal, J. Neurochem., 37:1345-48 (1981)) and has broad indications including narcolepsy, cataplexy, sleep paralysis, alcoholism, chronic schizophrenia, catatonic schizophrenia, atypical psychoses, chronic brain syndrome, neurosis, drug addiction and withdrawal, Parkinson's disease and other neuropharmacological illnesses, hypertension, ischemia, circulatory collapse, radiation exposure, cancer, myocardial infarction, anesthesia induction, sedation, growth hormone production, heightened sexual desire, anorectic effects, euphoria, smooth muscle relaxation, muscle mass production, and sleep.
Currently, sodium gamma-hydroxybutyrate is prescribed for patients with narcolepsy (Xyrem®, Orphan Medical) as a twice-nightly solution. Patients take an initial dose of sodium gamma-hydroxybutyrate around bedtime and must wake up four hours later to take a second dose. Such a dose regimen is rather inconvenient.
Other dosage forms of sodium gamma-hydroxybutyrate have also been disclosed. For example, U.S. Pat. No. 5,594,030 discloses controlled release pharmaceutical compositions of gamma hydroxybutyric acid salts consisting of a nucleus in the form of granulates or tablets which comprises GHB and a cellulosic matrix, wherein the drug substance is released within 7 to 8 hours.
Sodium gamma-hydroxybutyrate is highly soluble, hygroscopic, and strongly alkaline, and the therapeutic dose is normally very high. For example, a daily dose of 4.5 to 9 grams of Xyrem® is prescribed to narcolepsy patients. These characteristics of sodium gamma-hydroxybutyrate have some significant effects on coated particles or tablets comprising GHB. The high solubility of sodium gamma-hydroxybutyrate likely leads to drug migration into the coating layer during the coating process, and dissolves rapidly when the coated articles encounter water or bodily fluids, creating “pores” that allow leakage of the drug from the coated articles. Further, when sodium gamma-hydroxybutyrate penetrates/diffuses into the coating film, it may interfere with the coating material itself. For example, penetrated/diffused sodium gamma-hydroxybutyrate may act as a strong base which reacts with pH sensitive coating polymers, such as Eudragit L30-D55 for instance, weakening the coating layer and lowering the coating efficiency.
Further, the absorption of sodium gamma-hydroxybutyrate seems to be capacity-limited (Palatini et al, Eur. J Clin Pharmacol. (1993) 45:353-356), but it has been unclear whether the absorption of this drug is region-specific, which would affect the oral delivery of GHB.
Therefore, a need exists in the art for a more convenient dosing regimen, an effective dosage form of controlled release of gamma-hydroxybutyric acid salts and an efficient way to deliver gamma-hydroxybutyric acid salts to an animal in the gastrointestinal tract. The current invention satisfies these needs.